Increased platelet adhesion and thrombus formation in a mouse model of Alzheimer's disease
Increased platelet adhesion and thrombus formation in a mouse model of Alzheimer's disease
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DOI：
10.1016/j.cellsig.2016.08.017
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发表时间：
2016-12-01
影响因子：
4.8
通讯作者：
Torti, Mauro
中科院分区：
文献类型：
--
作者：
Canobbio, Ilaria;Visconte, Caterina;Torti, Mauro
血管功能障碍和阿尔茨海默病表现出显著的相似性和重叠性。心血管风险因素(高胆固醇血症、高血压、肥胖、动脉粥样硬化和糖尿病)会增加患血管性痴呆和阿尔茨海默病的风险。相反，阿尔茨海默氏症患者明显增加了缺血性和出血性中风的易感性。血小板是止血和血栓形成的主要参与者，并参与炎症。我们研究了3xTg-AD动物的血小板形态和功能，这是一种巩固的阿尔茨海默病小鼠模型。与年龄匹配的野生型小鼠相比，3xTg-AD老年小鼠的血小板在数量和糖蛋白表达方面都是正常的，但与年龄匹配的野生型小鼠的血小板相比，它们更能黏附在纤维胶原、von Willebrand因子、纤维蛋白原和淀粉样多肽等基质上。3xTg-AD洗涤的黏附于胶原蛋白的血小板也表现出对选定的信号蛋白的磷酸化增加，包括酪氨酸激酶Pyk2、PI3激酶效应器Akt、p38MAP激酶和肌球蛋白轻链激酶，以及在剪切下形成血栓的能力增加。相反，几种激动剂在3xTg-AD小鼠体内诱导的聚集和整合素αIIbβ3激活与野生型血小板相似。这些结果表明，阿尔茨海默氏症的突变导致循环中的血小板处于显著的过度激活状态，随着疾病的发展而明显。(C)2016 Elsevier Inc.保留所有权利。
Vascular dysfunctions and Alzheimer's disease show significant similarities and overlaps. Cardiovascular risk factors (hypercholesterolemia, hypertension, obesity, atherosclerosis and diabetes) increase the risk of vascular dementia and Alzheimer's disease. Conversely, Alzheimer's patients have considerably increased predisposition of ischemic and hemorrhagic strokes. Platelets are major players in haemostasis and thrombosis and are involved in inflammation. We have investigated morphology and function of platelets in 3xTg-AD animals, a consolidate murine model for Alzheimer's disease. Platelets from aged 3xTg-AD mice are normal in number and glycoprotein expression, but adhere more avidly on matrices such as fibrillar collagen, von Willebrand factor, fibrinogen and amyloid peptides compared to platelets from age-matching wild type mice. 3xTg-AD washed platelets adherent to collagen also show increased phosphorylation of selected signaling proteins, including tyrosine kinase Pyk2, PI3 kinase effector Akt, p38MAP kinase and myosin light chain kinase, and increased ability to form thrombi under shear. In contrast, aggregation and integrin alpha IIb beta 3 activation induced by several agonists in 3xTg-AD mice are similar to wild type platelets. These results demonstrated that Alzheimer's mutations result in a significant hyper-activated state of circulating platelets, evident with the progression of the disease. (C) 2016 Elsevier Inc. All rights reserved.